ITMI961628A1 - PROCEDURE FOR THE PREPARATION OF CEPHALOSPORINE - Google Patents

Description

Description of the industrial invention entitled: "PROCEDURE FOR THE PREPARATION OF CEPHALOSPORIN"

Field of the invention

The present invention relates to a process for the preparation of cephalosporins and in particular the preparation of 7- (a-hydroxyacylamino) - 3— (1-sulfoalkyl-tetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acids and their locations. The method involves the direct isolation, by lyophilization, of the active ingredient in pure form and ready for pharmaceutical use.

Previous technique

The 7- (α-hydroxyacylamino) -3- (1-sulfoalkyl-tetrazol-5-ilthiomethyl) -3-cefem-4-carboxylic acids are cephalosporan antibiotics having a marked antibacterial activity.

These cephalosporins are the subject of numerous patents, such as US 4,159,373, US 4,048,311 and US 4,093,723.

Of all the derivatives covered by these patents, Cefonicid, which is commercially available in the form of a lyophilized disodium salt, is of particular importance for its pharmaceutical activity.

A first known method for the preparation of Cefonicid involves the acylation of 7ACA (7-anminocephalosporanic acid) with a protected acylating agent and subsequent condensation with the desired tetrazoltiol and subsequent deprotection.

US patent 4,159,373 describes a series of preparations in which 7- (a-hydroxyacylamino) -3- (1-sulfoalkyl-tetrazol-5-yl-thiomethyl) -3-cefem-4-carboxylic acids are prepared by reaction of 7-a-hydroxyacylamino-cephalosporanic acids with tetrazol-thiol in water in the presence of sodium bicarbonate. The reaction products are recovered by passing the aqueous solutions, after acidification, over ion exchange resins and precipitating the sodium salts with sodium methoxide in methanol, or by chromatography on ion exchange resins, purification by precipitation in alcoholic solvents and lyophilization.

Another known method provides for the reaction of the desired tratrazoltiol with the 7-formamide derivative of 7ACA, subsequent deprotection and reaction with the suitably protected acylating agent.

The patents US 4,159,373 and US 4,576,937 already mentioned also describe the reaction of the 7-amnino-3- (1-sulphoalkyl-tetrazol-5-ilthiomethyl) -3-cefem-4-carboxylic acids with the chloride formyl ester of D-mandelic acid in anhydrous dimethylformairanide in the presence of triethylamine and subsequent deformylation in both base and acid-catalyzed aqueous environment.

WO 92/17600 describes the reaction of the appropriate cephalosporan nucleus with O-formylmandeloyl chloride in water in the presence of sodium bicarbonate and subsequent enzymatic deformylation.

EP-A-0156771 describes the preparation of 7- (a-hydroxyacylamino) -3- (1-sulfoalkyl-tetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acids by reaction of the appropriate cephalosporan nucleus with thioesters of D-mandelic acid and subsequent isolation of the formylated disodium salts, which are then transformed into the corresponding acid by passing over acidic ion exchange resins, retransformed into monosodium salts with sodium 2-ethylhexanoate and deformed with hydrochloric acid concentrated in methanol.

Finally, the final product is precipitated from the reaction mixture as a disodium seat after addition of sodium hydrate and isopropyl alcohol.

A more recent Italian patent application n. MI93A001580 reports, tracing what has already been described in US patent 4,159,373, the preparation of Cefonicid starting from 7-amino-3- (1-sulfoalkyl-tetrazol-5-yl-thiomethyl) -3-cefem-4-carboxylic acid by reaction with D-mandeloylformyl chloride and subsequent deprotection in hydrochloric acid.

The isolation of the product is carried out by extraction of the acid in an organic solvent, concentration of the same phase and precipitation of the disodium Cefonicid with sodium ethylhexanoate in an acetone-ethanol mixture.

The methods described in US 4,048,311, US 4,093,723 and 4,159,373 involve complex processes for separating the finished product and difficult industrial application.

The most recent WO 92/17600 and EP-A-0 156 771 describe synthesis methods simplified compared to previous patents, but also in this case the isolation of the finished product is still laborious, leads to the formation of colored mixtures and is difficult Hindu application.

The patent application n. MI93A001580 reports the preparation of Cefonicid by tracing what has already been described in the previous patents, but partly simplifying the recovery of the final product.

The isolation of Cefonicid is carried out by extraction, in an organic solvent, of the acid, subsequent concentration of the organic phase and precipitation of the disodium Cefonicid with sodium ethylhexanoate in an acetone-ethanol mixture. This method only partially solves the problems due to the formation of colored mixtures, as the concentration of the final organic solution, containing the product, is long and laborious. It should also be considered that the solvent envisaged for the extraction of Cefonicid is therefore to be concentrated under vacuum, it is the tetrahydrofuran of which the danger has arisen due to the probable formation of peroxides.

Furthermore, the disodium Cefonicid, which is obtained by precipitation of the acetone-ethanol mixture, has a high content of residual solvents and these remain in considerable quantities in the final product until after the subsequent freeze-drying phase.

Summary

The Applicant has found a process, which can be easily carried out on an industrial scale, which solves the known and aforementioned drawbacks for the preparation of 7-a-hydroxyacylamino cephalosporins of formula (I)

where is it

it is a phenyl group, optionally substituted by 1 to 3 substituents selected from halogens and hydroxyl groups, a heterocyclic ring of 4 to 7 atoms, both aromatic and non-aromatic, or a group selected from dihydrophenyl, cyclohexyl, hydroxymethyl, forming, acid and carboxymethylamino;

R2 is a linear or branched hydrogen or alkyl group having from 1 to 12 carbon atoms;

n is an integer from 1 to 10;

A and B, the same or different from each other, are pharmaceutically acceptable cations, for example cations of alkali or alkaline earth metals such as sodium, potassium and calcium or cations such as ammonium or organic amine cations.

The compounds of formula (I) have an asymmetric carbon atom in the side chain in position 7 of the "cephem" nucleus and can therefore be present in their D- or L- forms or in their mixtures.

The process of the invention comprises the following steps: a) condensation of the 7-amino-3-cephem-4-carboxylic acid of formula

(I)

in which R2 n have the meaning seen above, with the derivative fund of formula (III)

(III)

where R1 is as defined above;

the reaction is carried out in an organic or aqueous diluent medium or in mixtures of these at a pH between 6 and 7.0 by adding proton acceptors;

b) defomilation of the reaction product in the aqueous phase by treatment with an acid at pH 0.5-1.0 to give a product of formula (I)

c) adjustment of the pH of the aqueous solution with bases containing sodium a between 1.5 and 6.0 and osmotic filtration of the solution to remove excess sodium chloride;

d) optional adjustment of the pH to 5.2 with sodium-containing bases and lyophilization of the solution.

According to a preferred aspect of the invention, the product obtained from step b) is isolated by a process which comprises: e) the extraction of the acid product in organic solvent by salting the aqueous phase;

f) adjustment of the pH of the organic phase to pH between 1.5 and 2.5 with bases containing sodium, filtration of the solution and re-extraction of the product in the aqueous phase;

g) adjustment of the pH of the aqueous solution with sodium-containing bases at pH between 1.5 and 6.0 and osmotic filtration of the solution to remove excess sodium chloride;

h) optional adjustment of the pH to 5.2 with sodium-containing bases and lyophilization of the solution.

Detailed description

The method of the invention will now be described in greater detail with specific reference to Cefonicid.

The intermediates used in the synthesis of formulas (II) and (III) are known, commercially available or in any case can be easily prepared with processes described in patents or publications.

The first step consists of the acylation of 7-amino-3- (1-sulphoalkyl-tetrazol-5-yl-thiomethyl) -3-cefem-4-carboxylic acid with D-mandeloylformyl chloride.

The reaction can be carried out in water, in solvent or in a water-solvent mixture.

The solvents used are selected from acetone, methyl acetate, tetrahydrofuran, acetonitrile, dimethylacetamide.

The proton acceptor is an inorganic or organic base or a mixture thereof, preferably

triethylamine, tetramethylguanidine and diazobicicloundecene.

The acylation reaction is carried out in a temperature range between -5 ° C and 40 ° C, preferably between 0 ° and 10 ° C.

The reaction is preferably carried out in a water / acetone mixture in a ratio ranging from 70/30 to 30/70 using sodium bicarbonate as proton acceptor.

The very mild acylation conditions allow a perfect reproducibility of the reaction, eliminating the possibility of the formation of secondary products.

In this way clear solutions are obtained from which it is possible to extract a high quality product.

In the second step the acetone is removed from the reaction medium and the deformylation is carried out in an acid aqueous environment. The acetone can be removed by concentration under vacuum at temperatures between 20 ° and 40 ° C or extracted from the aqueous phase with solvents such as toluene, ethyl acetate, methyl isobutyl ketone, methylene chloride or chloroform.

Under the reaction conditions it is possible to perform the extraction with toluene.

The residual content of acetone in the aqueous phase after extraction is generally between 1 and 5%.

An acid is added to the aqueous solution containing the formylated salified product and the pH is brought to a value between 0.5 and 1.0. The deformilection is performed at a literature between 15 ° C and 30 ° C in a tarp between 20 and 48 hours.

The acid used for the deformylation can be inorganic such as hydrochloric acid, sulfuric acid or phosphoric acid or organic such as trifluoromethanesulfonic or methanesulfonic acid.

Preferably, hydrochloric acid is used at pH = 0.5 at 25 ° C for a total time of 20 hours.

Deformylation conditions are also particularly mild and such as to be highly selective. This makes it possible to drastically reduce the formation of unwanted secondary by-products.

The final deformylation mixture consists almost exclusively of Cefonicid and salts in aqueous solution.

In the next step the pH of the aqueous solution is brought to values between 1.5 and 6.0 with sodium-containing bases such as

and the solution is filtered by reverse osmosis on the membrane for

nanofritration. Filtration is carried out at a temperature between 5 ° C and 30 ° C at 10-40 bar. During filtration, distilled water is added to the solution containing the Cefonicid to keep the starting volume constant.

At the end of the osmotic filtration, two solutions are obtained, one rich in Cefonicid and the other in salts.

The solution containing the Cefonicid at a variable concentration between 15% and 50%, is brought to a pH between 4.5 and 6.0 with an inorganic base of your choice between and NaOH, is filtered on carbon, on a membrane sterilized from 0.22 μm and finally frozen at a temperature between -30 ° C and -60 ° C.

The frozen solution is freeze-dried at a vacuum between 10 and 400 μm, setting a heating temperature between 10 ° C and 70 ° C.

From the lyophilization process we obtain disodium Cefonicid with a high degree of purity ready for pharmaceutical use.

The conditions of acylation and deformylation adopted are very mild and allow to arrive at a solution containing almost exclusively Cefonicid and salts. The subsequent osmotic filtration conditions are also mild and allow to separate the pure form of Cefonicid in aqueous solution of the salts. This allows, through freeze-drying, to obtain a very pure product ready for pharmaceutical use and free from residual solvents such as acetone and alcohols.

The solvents used in some previous methods, to isolate the oral disodium Cefonicid, are difficult to eliminate both by drying the product under vacuum and by lyophilization of the same in aqueous solution.

The technique used in this invention eliminates the isolation of the oral product by precipitation and by using an osmotic filtration technique it allows to recover the product in pure form in aqueous solution.

The final lyophilization of the solution provides the Cefonicid disodium salt ready for pharmaceutical use.

In addition to having the aforementioned advantages, this process is simple and particularly convenient from an industrial point of view because it avoids the precipitation and isolation of the oral product which is very hygroscopic and difficult to dry.

The invention also relates to the isolation of Cefonicid after deformation by extraction in organic solvents such as acetone, THF, methyl acetate and acetonitrile by salting the aqueous solution.

After deformation, the pH of the aqueous solution is brought between 1.5 and 6.0 with inorganic bases, an organic solvent, preferably acetone, is added, and then the aqueous solution is saturated with sodium chloride.

Cefonicid from the aqueous phase passes into the organic solvent, decolouring charcoal is added, stirred and filtered.

In the next step the product is transferred in aqueous solution. Distilled water is added to the organic phase containing the Cefonicid and the organic solvent is removed from the solution either by concentration under vacuum at temperatures between 20 ° C and 40 ° C or by extraction of the aqueous phase with water-immiscible solvents such as toluene, acetate of ethyl, methyl isobutyl ketone, methylene chloride or chloroform.

Under the reaction conditions it is preferable to perform the extraction with toluene. In this way an aqueous solution containing Cefonicid and inorganic salts is obtained.

In the next step, the pH of the aqueous solution is brought to values between 1.5 and 6.0 and the solution is filtered by reverse osmosis on the membrane by nanofiltration.

Filtration is carried out at a temperature between 5 and 30 “C and at a pressure between 10 and 40 bar.

During filtration, distilled water is added to the solution containing the Cefonicid to keep the starting volume constant.

At the end of the osmotic filtration, two solutions are obtained, one rich in Cefonicid and the other in salts. The solution containing the Cefonicid, at a variable concentration between 15% and 50%, is brought to a pH between 4.5 and 6.0 with an inorganic base chosen between and NaOH, is filtered on cardboard and then on a sterilizing membrane 0.22 μm and finally frozen at a temperature between -30 ° C and -60 ° C.

The frozen solution is freeze-dried at a vacuum of less than 400 μm, preferably between 10 and 300 μm and setting a heating temperature between 10 ° C and 70 ° C. From the lyophilization process we obtain disodium Cefonicid with a high degree of purity ready for pharmaceutical use.

Also with this procedure the isolation of the oral product is eliminated by precipitation with the considerable advantages already mentioned, and allowing the recovery of the disodium Cefonicid by lyophilization in a very pure form.

Example 1

50 g of 7-amino-3- [sulphomethyl-1-H-tetrazol-5-yl) thiomethyl] -3-cefem-4-carboxylic acid are suspended in 125 cc of water and 350 cc of acetone.

It is cooled to 5 ° C and solubilized with 20 g of NaHC03 dissolved in 250 ml of water. To the perfectly clear solution are added at 5 ° C ± 1 ° C 22 ml of D - (-) - mandeloylformyl chloride dissolved in 50 ml of acetone maintaining the pH between 6.0 and 7.5 with subsequent additions of sodium bicarbonate solution.

It is left to react for 40 minutes at 5 ° C ± 1 ° C.

Once the reaction is complete, the acetone is extracted with 3x150 ml of toluene. Deformilation

The solution is acidified with concentrated HC1 at pH 0.5 and is left to stir for 20 hours at 25 ° C.

The acid solution is brought to pH 1.5 with sodium bicarbonate, washed again with 2x150 ml of toluene and decoloured with 2.5 g of oenological charcoal.

Osmotic filtration

The aqueous solution, 300 ml, is filtered at 20 ° C at 38 bar on a membrane by nanofiltration having a retention capacity for sodium chloride ≤ 50%.

The stock solution containing the Cefonicid is restored five times to the initial volume with distilled water and filtered again. Lyophilization

The concentrated solution, containing the product in a percentage of 30% -40%, is cooled to 10 ° C ± 2 ° C and brought to pH - 5.2 with sodium bicarbonate.

It is decoloured with 2.5 g of oenological charcoal and the solution is frozen at -40 ° C in a steel basin. The thickness of the frozen solution is 1.5 cm.

It is freeze-dried in 20 hours by bringing the temperature of the heating fluid to 45 ° C in 6 hours and leaving it freeze-dried at the same temperature for the remaining 14 hours. The vacuum used is 150 pm.

52 g of lyophilized disodium Cefonicid are obtained.

Kfisher = 1.5%

Chemical purity = 97% determined by HPLC

Residual solvents: traces.

50 g of 7-amino-3- [sulphomethyl-1-H-tetrazol-5-yl-thiomethyl] -3-cefem-4-carboxylic acid are suspended in 125 cc of water and 350 cc of acetone.

It is cooled to 5 ° C and solubilized with 20 g of NaHC03 dissolved in 250 ml of water. To the perfectly clear solution are added at 5 ° c ± 1 ° c 22 ml of D - (-) - mandeloylformyl chloride dissolved in 50 ml of acetone maintaining the pH between 6.0 and 7.5 with subsequent additions of sodium bicarbonate solution.

It is left to react for 40 minutes at 5 ° C ± 1 ° C.

Once the reaction is complete, the acetone is extracted with 3x150 ml of toluene. Deformilation

The solution is acidified with concentrated HC1 to pH - 0.5 and is left to stir for 20 hours at 25 ° C.

The acid solution is brought to pH - 5.2 with sodium bicarbonate washed again with 2x150 ml of toluene and decoloured with 2.5 g of oenological charcoal.

Osmotic filtration

The aqueous solution, 300 ml, is filtered at 20 ° C at 35 bar on a membrane by nanofritration having a retention capacity for sodium chloride <50%.

The stock solution containing the Cefonicid is restored five times to the initial volume with distilled water and filtered again. Lyophilization

The concentrated solution, containing the product in a percentage of 30% -40%, is cooled to 10 ° C ± 2 ° C, decoloured with 2.5 g of oenological charcoal and frozen at -40 ° C in a steel tray.

The thickness of the frozen solution is 1.5 cm.

It is freeze-dried in 20 hours, bringing the temperature of the heating fluid to 45 ° C in 6 hours and leaving it freeze-dried at the same temperature for the remaining 14 hours. The vacuum used is 150 μm.

54 g of lyophilized disodium Cefonicid are obtained.

Chemical purity = 98% determined by HPLC

Residual solvents: traces.

Example 3

50 g of 7-amino-3- [sulphomethyl-1-H-tetrazol-5-yl-thiomethyl] -3-cefem-4-carboxylic acid are suspended in 125 ml of water and 350 cc of acetone.

51 is cooled to 5 ° C and is solubilized with 20 g of dissolved in 250 ml of water. To the perfectly clear solution are added at 5 ° C ± 1 ° C 22 ml of D - (-) - mandeloylformyl chloride dissolved in 50 ml of acetone maintaining the pH between 6.0 and 7.5 with subsequent additions of sodium bicarbonate solution. It is left to react for 40 minutes at 5 ° C ± 1 ° C.

Once the reaction is complete, the acetone is extracted with 3x150 ml of toluene. Deformilation

The solution is acidified with concentrated HC1 to pH = 0.5 and is left to stir for 20 hours at 25 ° C.

The acid solution is brought to pH = 1.5 with sodium bicarbonate, washed again with 2x150 ml of toluene saturated with 120 g of sodium chloride and extracted with 3x150 ml of acetone.

The organic extracts are combined, 350 ml of H2O are added and the acetone is extracted with 3x150 ml of toluene.

Osmotic filtration

The aqueous solution, 300 ml, is filtered at 20 ° C and 38 bar on a membrane by nanofritration having a retention capacity for sodium clonir <50%.

The stock solution containing the Cefonicid is restored five times to the initial volume with distilled water and filtered again. Lyophilization

The concentrated solution, containing the product in a percentage of 30% -40%, is cooled to 10 ° C ± 2 ° C, brought to pH = 5.2 with NaHC03 and decoloured with 2.5 g of oenological charcoal.

It is frozen at -40 ° C in a 1.5 cm thick steel tray and freeze-dried in 20 hours bringing the temperature of the heating fluid to 45 ° C in 6 hours and leaving it freeze-dried at the same temperature for the remaining 14 hours. . The vacuum used is 150 μm.

54 g of lyophilized disodium Cefonicid are obtained.

Chemical purity = 98% determined by HPLC

Residual solvents: traces.

Example 4

50 g of 7-amino-3- [sulphomethyl-1-H-tetrazol-5-yl-thiomethyl] -3-cefem-4-carboxylic acid are suspended in 125 ml of water and 350 cc of acetone.

It is cooled to 5 ° C and solubilized with 20 g of NaHC03 dissolved in 250 ml of water. To the perfectly clear solution, add 22 ml of D - (-) - mandeloylformyl chloride dissolved in 50 ml of acetone at 5 ° C ± 1 ° C, maintaining the pH between 6.0 and 7.5 with subsequent additions of sodium bicarbonate solution. The reaction is allowed for 40 minutes at 5 <°> C i 1 ° C.

Once the reaction is complete, the acetone is extracted with 3x150 ml of toluene. Deformilation

The solution is acidified with concentrated HC1 to pH = 0.5 and is left to stir for 20 hours at 25 ° C.

The acid solution is brought to pH = 1.5 with sodium bicarbonate, washed again with 2x150 ml of toluene saturated with 120 g of sodium chloride and extracted with 3x150 ml of acetone.

The organic extracts are combined, 350 ml of H2O are added and the acetone is extracted with 3x150 ml of toluene. The acidic aqueous solution is brought to pH = 5.2 with sodium bicarbonate, washed again with 2x150 ml of toluene and decoloured with 2.5 g of carbon.

Osmotic filtration

The aqueous solution, 300 ml, is filtered at 20 ° C and 38 bar on a membrane by nanofiltration having a retention capacity for sodium chloride <50%.

The stock solution containing the Cefonicid is restored five times to the initial volume with distilled water and filtered again.

Lyophilization

The concentrated solution, containing the product in a percentage of 30% -40%, is cooled to 10 ° C ± 2 ° C and decoloured with 2.5 g of oenological charcoal.

It is frozen at -40 ° C in a 1.5 cm thick steel tray and freeze-dried in 20 hours bringing the temperature of the heating fluid to 45 ° C in 6 hours and leaving it freeze-dried at the same temperature for the remaining 14 hours. .

The vacuum used is 150 μm).

54 g of lyophilized disodium Cefonicid are obtained.

Chemical purity = 98% determined by HPLC

Residual solvents: traces.

Claims (20)

CLAIMS 1. Procedure for the preparation of cephalosporins of formula (I) R1 is a phenyl group, optionally substituted by 1 to 3 substituents selected from halogens and hydroxyl groups, a heterocyclic ring from 4 to 7 atoms, both aromatic and non-aromatic, or a group selected from dihydrophenyl, cyclohexyl, hydroxymethyl, forming, acid and carboxymethylamino ; R2 is a linear or branched hydrogen or alkyl group having from 1 to 12 carbon atoms; n is an integer from 1 to 10; A and B can be the same or different from each other, they are pharmaceutically acceptable cations and can be for example cations of alkaline or alkaline earth metals such as sodium, potassium and calcium or cations such as harmonium or organic harmine cations, which includes the following steps: a) condensation of 7-amino-3-cephem-4-carboxylic acid of formula (II) in which R2 and n have the meaning seen above, with formyl derivatives of formula (III) (III) in an organic or aqueous diluent medium or in mixtures thereof, at a pH between 6 and 7 by adding a proton acceptor; b) deformylation of the reaction product in the aqueous phase by treatment with an acid at pH 0, 5-1.0 to give a product of formula (I) c) adjustment of the pH of the aqueous solution with bases containing sodium type pH between 1.5 and 6.0 and osmotic filtration of the solution to remove excess sodium chloride; d) adjustment of the pH of the solution, residual of osmotic filtration, to values between 4.5 and 6.5 and lyophilization. 2. Process according to claim 1, stages a) and b) wherein the product obtained from stage b) is isolated by a process which comprises: e) the extraction of the acid product in organic solvent by salting the aqueous phase; f) pH adjustment of the organic phase to pH between 1.5 and 2.5 with sodium-containing bases, filtration of the solution and re-extraction of the product in the aqueous phase; g) pH adjustment of the aqueous solution with sodium-containing bases at pH between 1.5 and 6.0 and osmotic filtration of the solution to remove excess sodium chloride; h) optional adjustment of the pH to 5.2 with sodium-containing bases upon lyophilization of the solution. 3. Process according to claim 1 or 2 for the preparation of Cefonicid. 4. Process according to one of claims 1 to 3, wherein step a) is carried out in acetone, methyl acetate, tetrahydrofuran, acetonitrile, water or in a mixture of these and the proton acceptor is selected from and triethylamine, tetramethylguanidine and diazobicicloundecene. 5. Process according to one of the preceding claims, in which step a) is carried out at temperatures between 0 ° C and 15 ° C. 6. Process according to one of the preceding claims, in which step a) is carried out in a water / acetone mixture in a volumetric ratio ranging from 30/70 to 70/30, using sodium bicarbonate as proton acceptor. 7. Process according to one of the preceding claims, wherein the deformylation is carried out at pH between 0.5 and 1.5 in the aqueous phase in the presence of organic or inorganic acids such as HCl, H2SO4, H3PO4, methanesulfonic acid and trifluoroacetic acid. 8. Process according to claim 6, wherein the acetone is removed from the acetone / water mixture by extraction with toluene. 9. Process according to one of the preceding claims, in which the deformylation is carried out between 20 ° C and 40 ° C with hydrochloric acid at pH -0.5. 10. Process according to one of the preceding claims in which step c) is carried out by adjusting the pH of the solution to values between 1.5 and 6.0 with and the solution is filtered on a membrane by nanofiltration at temperatures between 0 ° C and 50 ° C at a pressure of 10-50 bar. 11. Process as claimed in claim 10, wherein the pH of the aqueous solution is adjusted to 1.5 or 5.2 and the base used is sodium bicarbonate. 12. Process as claimed in claim 10, wherein the aqueous solution containing the product is filtered on a membrane by nanofiltration having a retention capacity for sodium chloride <50% at a temperature of 20 ° C and a pressure of 38 bar. 13. The method claimed in claim 1, wherein step d) is performed by adjusting the pH of the solution to 4.5-6.5 with o NaOH at a temperature between 0 ° C and 50 ° e e la lyophilization performed by freezing the solution at -40 ° C and 60 ° C and subsequent heating of the fluid at 40 ° C and 70 ° C and a freeze-drying vacuum of less than 300 μm. 14. A process according to claim 13, wherein the solution is adjusted to 5.2 with sodium bicarbonate. 15. Process according to claim 13, wherein the pH adjustment is carried out at 10 ° C. 16. Process according to claim 2, wherein step f) is carried out by adding water to the organic phase containing the active principle and removing the first by extraction with solvents selected from toluene, ethyl acetate, methylisobutylketone, methylene chloride, chloroform. 17. Process according to claim 2, wherein step g) is carried out by adjusting the 01 of the aqueous solution to values between 1.5 and 6.0 with standard bases and NaOH and filtration of the solution on the membrane by nanofritration at temperatures comprised between 0 ° and 50 ° c and pressure of 10-40 bar. 18. Process according to claim 17, wherein the O1 of the aqueous solution is adjusted to 1.5 or 5.2 and the base used is sodium bicarbonate. 19. Process according to claim 18, wherein the aqueous solution containing the product is filtered on a membrane by nanofiltration having a retention capacity for sodium chloride <50% at a temperature of 20 ° C and a pressure of 38 bar. 20. Process according to claim 2, wherein step g) is carried out by adjusting the pH of the solution to 4.5-6.5 with o NaOH at a temperature between 0 ° and 50 ° C and freeze-drying is performed by freezing the solution at -40 ° C and -60 ° C, subsequent heating of the fluid to 40 ° C and 70 ° C and a freeze-drying vacuum less than 300 μm.